관심 일도 없다가... 어떤 분들은 불가능하다.. 어떤 분들은 니가 못한다고 남이 못하냐.. 라고 하길래..
뭐.. 애가 적을 수도 잇는거 아닌가? 대체 무슨 내용이길래 다들 그러지..하면서
단어만 의학 단어 줄줄 들어 있어서 어렵게 느껴져서 그렇지 실상 별것도 아닌거 아닌가? 하는 생각도 들고..
호기심에서 저도 한번 읽어봅니다.
심심하신 분들은 같이 읽어요.
https://www.jpatholtm.org/upload/pdf/kjp-43-4-306.pdf?fbclid=IwAR2X4SUFYSMlHxrT-csY0H2YCWz11RWfo1UllDwUMx9zxovWBMfSEz0ETKM
Nitric oxide (NO) is produced from the oxidation of L-arginine to L-citrulline by NO synthase (NOS).1 Endothelial cells are able to produce NO via endothelial NOS (eNOS), which has an important physiologic role in regulating vascular tone.2 Moreover, NO modulates smooth muscle cell proliferation and attenuates leukocyte adhesion to the endothelium, as well as inhibition of platelet aggregation.3 NO plays an important role in the pathogenesis of many human cardiovascular diseases.4,5 The reduced production and activity of basal NO may predispose to hypertension, thrombosis, vasospasm, and atherosclerosis in humans.6,7 The amount of NO production in the vessels may closely correlate with the extent of eNOS expression, as controlled by the eNOS gene.8 Thus, investigation of the variability of eNOS polymorphisms may elucidate the genetic association with many human vascular diseases, such as ischemic heart disease and cerebrovascular diseases.9-11 The polymorphisms of the eNOS gene have been previously investigated in both people of advanced age and among various ethnic groups in association with stroke.12-16 Although some of these studies reported conflicting results, the association of eNOS polymorphisms was consistently correlated with stroke.15,16 The eNOS gene is located on chromosome 7q35-36 and is comprised of 26 exons spanning 21 kb.17 Among the several polymorphisms of the eNOS gene, three types have been investigated to detect a link with cerebrovascular disease: the Glu298Asp polymorphism in exon 7, the variable number of tandem repeats [VNTR, 27 bp repeat] polymorphism in intron 4, and the T-786C polymorphism in the 5′-flanking region of eNOS.12-14,17 Perinatal hypoxic-ischemic encephalopathy (HIE), which is most commonly recognized in newborn infants during delivery, is a significant cause of severe, long-term neurologic deficits. Impaired cerebral blood flow during perinatal HIE has been demon- 306 The Korean Journal of Pathology 2009; 43: 306-11 DOI: 10.4132/KoreanJPathol.2009.43.4.306 Background : In perinatal hypoxic-ischemic encephalopathy (HIE), cerebral blood flow is impaired and the activity of nitric oxide systhase (NOS) is markedly increased. For the association with the development of a stroke, the endothelial NOS (eNOS) polymorphisms are wellknown. Methods : Three clinically relevant polymorphisms of the eNOS gene were determined in 37 term/near-term infants with perinatal HIE (HIE group) and 54 normal term newborn infants without any perinatal problems (control group) using a polymerase chain reaction with or without restriction fragment enzyme digestion. The differences in the genotype, allele, and haplotype frequencies were evaluated between the groups. Results : The analysis of the allele frequencies showed that the G allele of Glu298Asp was more frequent in the HIE group than in the controls. The comparisons between the controls and each subgroups with complications that occurred with HIE showed that the TC genotype and C allele of T-786C were more common in patients with persistent pulmonary hypertension of the newborn (PPHN) than in the controls. The frequency of the A b T haplotype was lower in the HIE patients than in the controls. Conclusions : The G allele of Glu298Asp was associated with perinatal HIE, while the TC genotype and C allele of T-786C were associated with PPHN. Key Words : Nitric oxide; Endothelial NOS (eNOS); Genetic polymorphism; Hypoxic-ischemic encephalopathy; Newborn; Infant; Persistent pulmonary hypertension of the newborn (PPHN) Min Cho1 ∙Kwang-Sun Hyun1 David Chanwook Chung2 In-Young Choi3 ∙Myeung Ju Kim1,3 Young Pyo Chang2 306 eNOS Gene Polymorphisms in Perinatal Hypoxic-Ischemic Encephalopathy Corresponding Author Young Pyo Chang, M.D. Department of Pediatrics, College of Medicine, Dankook University, San 29 Anseo-dong, Cheonan 330-714, Korea Tel: 041-550-3937 Fax: 041-550-3905 E-mail:ychang@dankook.ac.kr *This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF2006-331-E00163). 1 Institute of Medical Science, Departments of 2 Pediatrics and 3 Anatomy, Dankook University College of Medicine, Cheonan, Korea Received : December 11, 2008 Accepted : March 20, 2009 eNOS Polymorphisms in Hypoxia-ischemia 307 strated and associated with the activity of NO.18 Increased NO production by the endothelium leads to cerebral vasodilation; this results in an increase in cerebral blood flow, which may be protective.19 However, during episodes of ischemia, increased cerebral blood flow caused by the vasodilatory effect of NO may cause reperfusion injury.20 In addition, during hypoxia-ischemia episodes, excessive production of NO will react with superoxide and then generate a potent radical, peroxynitrite, which activates lipid peroxidation and induces neuronal injury.20 For patients with perinatal HIE, the variability of the eNOS polymorphisms may affect both eNOS activity and NO production in the brain of newborn infants, which may result in different clinical results manifested by the severity of the perinatal HIE. However, there are no prior reports on eNOS polymorphisms and perinatal HIE. Therefore, the present investigation evaluated the clinically relevant polymorphisms of the eNOS gene in perinatal HIE by using a PCR with or without restriction enzyme digestion. In addition, we also assessed the association of complications of perinatal HIE with eNOS polymorphisms. MATERIALS AND METHODS Experimental subjects This study included 37 term or near-term newborn infants with moderate-to-severe perinatal HIE (HIE group) and 54 normal full-term newborn infants without any perinatal problems (control group) who were admitted to the neonatal intensive care unit (NICU) or nursery of Dankook University Hospital between 2002 and 2004. All infants with perinatal HIE fulfilled the diagnostic criteria for perinatal asphyxia21 and manifested an acute encephalopathy associated with perinatal asphyxia. The clinical course of HIE was moderate-to-severe for all affected infants according to the Sarnat classification.22 The gestational age of the infants with HIE was >36 weeks and the Apgar scores at 5 min were <7, and the blood gases were acidic (pH<7.2), hypoxemic, and/or hypercapnic. Infants with a major congenital anomaly, intrauterine chronic infection, proven sepsis, multiple births, and postmaturity were not included. All infants were ethnically homogenous Koreans who were unrelated. Informed consent was obtained from the parents of all infants. The study was approved by the Institutional Review Board of Dankook University Hospital. DNA extraction and genotyping Peripheral blood samples were drawn and the blood added to an EDTA tube; genomic DNA was extracted from the blood leukocytes. The three clinically relevant polymorphisms of the eNOS gene were determined in all infants as previously described.9 Genotyping for Glu298Asp in exon 7 was determined by PCR amplification using a set of forward and reverse primers (5′-AAG GCA GGA GAC AGT GGA TGG A-3′and 5′-CCC AGT CAA TCC CTT TGG TGC TCA-3′, respectively). The amplified 258-bp fragment was digested with the restriction enzyme, BanII, resulting in the fragment either being digested into 2 fragments, a 163 bp and a 85 bp fragment (wild-type allele ‘‘G’’), or not being digested (variant allele ‘‘A’’). These fragments were analyzed by 12% acrylamide gel electrophoresis, and visualized by silver staining. For detection of the T-786C polymorphism in the 5′-flanking region of eNOS the forward and reverse primers, 5′-TGG AGA GTG CTG GTG TAC CCC A-3′and 5′-GCC TCC ACC CCC ACC CTG TC-3′, were respectively used in the PCR. The amplified products were digested with MspI, producing fragments of 140 bp and 40 bp for the wildtype allele (allele ‘‘T’’), or 90, 50, and 40 bp in the case of a variant (allele ‘‘C’’). The fragments were separated by 12% acrylamide gel electrophoresis, and visualized by silver staining. Detection of the VNTR polymorphism in intron 4 was performed by PCR using the forward and reverse primers, 5′-AGG CCC TAT GGT AGT GCC TTT-3′and 5′-TCT CTT AGT GCT GTG GTC AC-3′, respectively. The PCR products were separated by 2.5% agarose gel electrophoresis and visualized by ethidium bromide staining. The 420 bp wild type product contained five 27 bp repeats (the ‘‘b’’ allele), and the 393 bp variant contained four 27 bp repeats (the ‘‘a’’ allele). Genotyping for three polymorphisms of the eNOS gene is shown in Fig. 1. The genotype 4aa of VNTR and CC of T-786C were not detected in any of the infants included in this study. Statistical analysis The data were analyzed using the SPSS statistical package program, version 14.0 for Windows (SPSS Inc, Chicago, IL, USA). The observed frequencies of the genotypes were compared with the frequencies expected under Hardy-Weinberg equilibrium by the 2 test. The differences in the genotype, allele, and haplotype frequencies between groups were evaluated by the 2 test, Student’s t-test, or Fisher’s exact test, as indicated. Values of p< 0.05 were considered significant, and these were corrected in 308 Min Cho∙Kwang-Sun Hyun∙David Chanwook Chung, et al. certain cases by multiplying the values by the number of alleles investigated (pcorr). The odds ratio (OR) and 95% confidence interval (CI) were also determined as indicated. RESULTS The clinical characteristics of infants included in this study are presented in Table 1. The mean birth weight and gestational age were not significantly different between the HIE and control groups. Both the 1 and 5 min Apgar scores were significantly lower in the HIE group than in the control group (p<0.05). The number of HIE infants born in another or outside hospital was 21 (56.8%), but there were none in the control group. Cesarean section was performed in 22 (59.5%) cases in the HIE group and in 15 (27.8%) in the control group (p<0.05). Meconium staining and fetal distress associated with birth asphyxia were only observed in the HIE group. The genotype and allele frequencies of the three investigated polymorphisms of the eNOS gene are shown in Table 2. The genotype frequencies of the polymorphisms in each group were consistent with Hardy-Weinberg equilibrium. The distributions of genotypes in relationship to the three polymorphisms were not significantly different between the controls and the HIE group. In the analysis of allele frequencies, the G allele of Glu298Asp was more frequent in the HIE group than in the control group (pcorr=0.036). The OR of the G allele for the HIE group was 8.28 (95% CI, 1.05-65.57). The HIE complication subgroup compared to the controls showed that the TC genotype and C allele of the T-786C were more frequently observed in the babies with persistent pulmonary hypertension of the newborn (PPHN) group than in the controls (p=0.001 and pcorr=0.002, respectively). The ORs of the TC genotype and C allele with regard Glu298Asp Genotypes AA GA GG 258 bp 163 bp 85 bp T-786C Genotypes TT TC TT 140 bp 90 bp 50 bp 40 bp VNTR Genotypes 4bb 4bb 4ba 4bb 420 bp 393 bp Fig. 1. Genotyping for the Glu298Asp polymorphism in exon 7, for the T-298C polymorphism in the 5′-flanking region and VNTR polymorphism in intron 4 of eNOS. The PCR products were digested with restriction enzymes producing different fragments leading to specific genotypes. The genotype 4aa of VNTR and CC of T-786C were not detected in the infants studied. Perinatal HIE (n=37) Control (n=54) Birth weight (g) 2,972.8±617.0 3,143.9±432.6 Gestational age (weeks) 38.0±2.8 38.3±1.5 Apgar score at 1 min* 3.6±1.7 8.3±0.8 Apgar score at 5 min* 5.0±1.4 9.5±0.6 CS* 22 (59.5%) 15 (27.8%) BOH* 21 (40.7%) 0 (0.0%) Meconium staining* 9 (24.3%) 0 (0.0%) Fetal distress* 7 (18.9%) 0 (0.0%) *p<0.05, which are obtained from comparison HIE with control group. HIE, hypoxic ischemic encephalopathy; CS, cesarean section; BOH, born in another or outside hospital. Table 1. Clinical characteristics of infants included in this study Control All (%) (n=54) Perinatal HIE with complication All (%) (n=37) MAS (%) (n=10) SZ (%) (n=10) PPHN (%) (n=4) RDS (%) (n=8) Genotype GG 45 (83.3) 36 (97.3) 9 (90.0) 8 (100.0) 4 (100.0) 10 (100.0) GA 7 (13.0) 1 (2.7) 1 (10.0) 0 (0.0) 0 (0.0) 0 (0.0) AA 2 (3.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 4bb 46 (85.2) 28 (75.7) 8 (80.0) 7 (87.5) 2 (50.0) 8 (80.0) 4ba 8 (14.8) 9 (24.3) 2 (20.0) 1 (12.5) 2 (50.0) 2 (20.0) 4aa 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) TT 48 (88.9) 30 (81.1) 8 (80.0) 5 (62.5) 1 (25.0) 10 (100.0) TC 6 (11.1) 7 (18.9) 2 (20.0) 3 (37.5) 3 (75.0)* 0 (0.0) CC 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Allele frequency G 89.8 98.6� 95.0 100 100 95.0 A 10.2 1.4 5.0 0.0 0.0 5.0 b 92.6 87.8 90.0 93.8 75.0 90.0 a 7.4 12.2 10.0 6.3 25.0 10.0 T 94.4 90.5 90.0 81.3 62.5 100.0 C 5.6 9.5 10.0 18.7 37.5� 0.0 *p=0.001, OR=24.00 (95% CI; 2.14, 269.11); � pcorr=0.036, OR=8.28 (95% CI; 1.05, 65.57); � pcorr=0.002, OR=10.20 (95% CI; 1.96, 53.18), which are obtained from comparison with control group. n, number of subjects; HIE, hypoxic ischemic encephalopathy; OR, odds ratio; CI, confidence interval; MAS, meconium aspiration syndrome; RDS, respiratory distress syndrome; PPHN, persistent pulmonary hypertension syndrome; SZ, seizure. Table 2. Genotype distribution and allele frequencies of eNOS gene in perinatal HIE and control groups eNOS Polymorphisms in Hypoxia-ischemia 309 to PPHN were 24.00 (95% CI, 2.14-269.11) and 10.20 (95% CI, 1.96-53.18), respectively. Among the 8 haplotypes of the eNOS polymorphism, the 5 with frequencies >5% are presented in Table 3. Comparisons of the haplotype frequencies were only conducted between the control and the HIE group. Frequency of the A b T haplotype was significantly lower in the HIE group than in the control group (p=0.029). The OR of the A b T haplotype with regard to HIE was 0.12 (95% CI, 0.02-0.96). DISCUSSION NO has a significant role in the pathogenesis of several neonatal diseases related to perinatal events, such as HIE, bronchopulmonary dysplasia, intraventricular hemorrhage, retinopathy of prematurity (ROP), and necrotizing enterocolitis. NO has been shown to modulate the degree of cerebral ischemia following stroke by regulating cerebral blood flow.23 However, the correlation of eNOS with the clinical manifestations of perinatal and neonatal diseases remains to be elucidated. Recently, eNOS 27-bp repeat polymorphism has been suggested to have a functional association with the risk of severe ROP.24 Thus, analysis of the eNOS gene may provide insight into the correlation of the important genetic polymorphisms associated with HIE and its complications. Several studies on the eNOS gene have shown a strong correlation with cerebrovascular disease and the associated clinical manifestations, disease course, and complications.15,16 However, previous studies showed little correlation between the Glu298Asp polymorphism in exon 7 and ischemic cerebrovascular disease.10,13 In addition, another group insisted that the 27 bp repeat VNTR polymorphism in intron 4 was not a risk factor for cerebrovascular disease in a Japanese study.14 Nevertheless, an association between brain infarction, especially lacunar infarction, and homozygosity for the G allele of the Glu298Asp polymorphism in exon 7 was suggested.15 A study on lacunar infarction without leukoaraiosis also showed an association with the VNTR polymorphism located in intron 4.25 Moreover, the T-786C polymorphism in the eNOS 5′-flanking region was considered a risk factor for an ischemic stroke.16 Consistent with these previous findings, the present study showed a possible association between the G allele of Glu298Asp in exon 7 and perinatal HIE, although the small sample size in this study limits the interpretation of this finding. The frequency of the G allele in cerebrovascular disease, including perinatal HIE, may be explained by the role of NO in the pathogenesis of HIE. Thus, just as for a brain infarction in the older population, the G allele might be a risk factor for perinatal HIE, and the clinical severity of perinatal HIE appears to be associated with eNOS genetic variations.15 Four infants, with PPHN as a complication of HIE, were investigated in this study. At birth, eNOS activity may play a pivotal role in maintaining vasodilatory pulmonary adaptation. However, the inhibition or decreased expression of eNOS may result in PPHN-like disease.26 Thus, the failure of pulmonary vasodilatory adaptation at birth stimulates pulmonary artery constriction as a common perinatal event. The pulmonary hypertension resulting from pulmonary vasoconstriction, with a right-to leftshunt via the ductus arteriosus and/or foramen ovale, is the main pathognomic finding of PPHN.27 Hence, as a clinical treatment for PPHN, NO inhalation is usually used to selectively dilate the pulmonary arteries.27 A previous study on eNOS genetic variations demonstrated that the expression of the eNOS gene was decreased in PPHN. In addition, the mRNA of eNOS was not detected in the endothelial cells of infants with PPHN.26 In our study, the TC genotype and C allele of T-786C appeared to be risk factors for PPHN occurring as a complication of HIE. However, there is a limitation to say in this study that the TC genotype and C allele of T-786C have functional correlations with decreased NO production, since we did not attempt to assess plasma nitrite and nitrate (NOx) levels and/or changes in activity of enzyme. A few studies28-30 showed the correlation of the genetic polymorphism in the eNOS gene with NOx levels. Recently, the study on the eNOS variants and 4-locus haplotypes associated with essential hypertension demonstrated the decrease of NOx in the patients than controls, which were statistically significant (p<0.0001).30 They also suggested that the eNOS variants can be used as markers of increased susceptibility to the risk of essential hypertension.30 This is the first study to show a relationship between the G allele of Glu298Asp in exon 7 of the eNOS gene and perinatal Haplotypes Control (%) Perinatal HIE (%) p-value OR (95% CI) G b T 83.3 83.8 0.936 1.033 (0.47, 2.30) G b C 5.6 1.0 0.315 1.78 (0.57, 5.52) G a T 7.4 12.2 0.279 1.73 (0.64, 4.72) G a C 5.6 5.4 0.965 0.97 (0.26, 3.57) A b T 10.2 1.4 0.029 0.12 (0.015, 0.96) HIE, hypoxic ischemic encephalopathy; OR, odds ratio; CI, confidence interval. Table 3. Haplotype frequencies of eNOS gene in perinatal HIE and control groups 310 Min Cho∙Kwang-Sun Hyun∙David Chanwook Chung, et al. HIE. In addition, the TC genotype and C allele of T-786C were observed to be associated with PPHN, a complication of HIE. Further investigation with a large number of HIE patients with PPHN are needed to confirm the genetic significance of eNOS polymorphisms and evaluate the genetic effects of eNOS on neonatal diseases. REFERENCES 1. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988; 333: 664-6. 2. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 1987; 84: 9265-9. 3. Radomski MW, Palmer RM, Moncada S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci U S A 1990; 87: 5193-7. 4. Warren JB, Pons F, Brady AJ. 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No association between Glu/Asp polymorphism of NOS3 gene and ischemic stroke. Neurology 1999; 53: 418-20. 11. de Syllos RW, Sandrim VC, Lisboa HR, Tres GS, Tanus-Santos JE. Endothelial nitric oxide synthase genotype and haplotype are not associated with diabetic retinopathy in diabetes type 2 patients. Nitric Oxide 2006; 15: 417-22. 12. Grewal RP, Dutra AV, Liao YC, Juo SH, Papamitsakis NI. The intron 4c allele of the NOS3 gene is associated with ischemic stroke in African Americans. BMC Med Genet 2007; 8: 76. 13. Markus HS, Ruigrok Y, Ali N, Powell JF. Endothelial nitric oxide synthase exon 7 polymorphism, ischemic cerebrovascular disease, and carotid atheroma. Stroke 1998; 29: 1908-11. 14. Yahashi Y, Kario K, Shimada K, Matsuo M. The 27-bp repeat polymorphism in intron 4 of the endothelial cell nitric oxide synthase gene and ischemic stroke in a Japanese population. Blood Coagul Fibrinolysis 1998; 9: 405-9. 15. Elbaz A, Poirier O, Moulin T,Che@dru F, Cambien F, Amarenco P. 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Care of the high-risk infant. In: Taeusch HW, Ballard RA, Gleason CA, eds. Avery’s disease of the newborn. 8th ed. Philadelphia: Elsevier, 2005; 349-63. 22. Sarnat HB, Sarnat MS. Neonatal encephalopathy following foetal distress: a clinical and electroencephalography study. Arch Neurol 1976; 33: 696-705. 23. Andresen J, Shafi NI, Bryan RM Jr. Endothelial influences on cerebrovascular tone. J Appl Physiol 2006; 100: 318-27. 24. Rusai K, Vannay A, Szebeni B, et al. Endothelial nitric oxide synthase gene T-786C and 27-bp repeat gene polymorphisms in retinopathy of prematurity. Mol Vis 2008; 14: 286-90. 25. Hassan A, Gormley K, O’Sullivan M, et al. Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease. Stroke 2004; 35: 654-9. 26. Villanueva ME, Zaher FM, Svinarich DM, Konduri GG. Decreased gene expression of endothelial nitric oxide synthase in newborns with persistent pulmonary hypertension. Pediatr Res 1998; 44: 338-43. 27. Shaul PW, Farrar MA, Magness RR. Pulmonary endothelial nitric oxide production is developmentally regulated in the fetus and newborn. Am J Physiol 1993; 265: H1056-63. 28. Tsukada T, Yokoyama K, Arai T, et al. Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in humans. Biochem Biophys Res Commun 1998; 245: 190-3. eNOS Polymorphisms in Hypoxia-ischemia 311 29. Nejatizadeh A, Kumar R, Stobdan T, et al. Endothelial nitric oxide synthase gene haplotypes and circulating nitric oxide levels significantly associate with risk of essential hypertension. Free Radic Biol Med 2008; 44: 1912-8. 30. Tanus-Santos JE, Desai M, Deak LR, et al. Effects of endothelial nitric oxide synthase gene polymorphisms on platelet function, nitric oxide release, and interactions with estradiol. Pharmacogenetics 2002; 12: 407-13.
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